Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) is etiologically associated with several AIDS-related malignancies including Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). In AIDS patients, oral KS is a common manifestation and often the first pathological symptom to appear, but KS frequently evolves into fatal stages involving visceral organs. Despite the success of HAART in some developed countries, KS remains an important disease of morbidity and mortality in US and worldwide. Understanding the mechanism of KSHV-induced pathogenesis could provide a scientific basis for developing novel preventive and therapeutic targets for KSHV-related malignancies. Current evidences indicate that KSHV lytic replication and the resulting constant new infection are important for sustaining the growth of KS tumors. Thus, it is essential to understand the molecular mechanisms and signaling pathways that regulate KSHV infection and replication. Our preliminary studies have shown that KSHV activates MEK, JNK and p38 multiple mitogen-activated protein kinase (MAPK) pathways during primary infection. Importantly, inhibitors of all three MAPK pathways reduce KSHV infectivity and the production of infectious virions during productive primary infection of primary human umbilical vein endothelial cells (HUVEC), and KSHV reactivation in latently-infected PEL cells. Based on these results, we hypothesize that multiple MAPK pathways regulate KSHV infection and replication during productive primary infection and reactivation from latency. To test this hypothesis, we will define the molecular mechanisms by which multiple MAPK pathways regulate KSHV infectivity (Aim I), KSHV lytic replication during productive primary infection (Aim II), and KSHV reactivation from latency (Aim III). The proposed study is highly significant because it will not only help understand the cellular pathways and mechanisms controlling KSHV infection and replication but also identify potential novel therapeutic targets.